Open AccessEffects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation
Author(s) -
Galloway Dylan A.,
Williams John B.,
Moore Craig S.
Publication year - 2017
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.414
Subject(s) - dimethyl fumarate , oligodendrocyte , astrocyte , antioxidant , multiple sclerosis , cancer research , microbiology and biotechnology , medicine , immunology , chemistry , biology , biochemistry , central nervous system , endocrinology , myelin
Objective Dimethyl fumarate ( DMF ) is a fumaric acid ester approved for the treatment of relapsing‐remitting multiple sclerosis ( RRMS ). In both the brain and periphery, DMF and its metabolite monomethyl fumarate ( MMF ) exert anti‐inflammatory and antioxidant effects. Our aim was to compare the effects of DMF and MMF on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system ( CNS ). Direct effects of fumarates on neural progenitor cell ( NPC ) differentiation toward the oligodendrocyte lineage were also assessed. Methods Primary astrocyte cultures were derived from both murine and human brains. Following pretreatment with MMF , DMF , or vehicle, astrocytes were stimulated with IL ‐1 β for 24 h; gene and micro RNA expression were measured by qPCR . Cytokine production and reactive oxygen species ( ROS ) generation were also measured. NPC s were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers. Results In both murine and human astrocytes, DMF , but not MMF , significantly reduced secretion of IL ‐6, CXCL 10, and CCL 2; neither fumarate promoted a robust increase in antioxidant gene expression, although both MMF and DMF prevented intracellular ROS production. Pretreatment with fumarates reduced micro RNA s ‐146a and ‐155 upon stimulation. In NPC cultures, DMF increased the number of O4 + and NG 2 + cells. Interpretation These results suggest that DMF , and to a lesser extent MMF , mediates the anti‐inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed CNS , DMF may be the active compound mediating the anti‐inflammatory effects independent from altered antioxidant gene expression.